Stereoselective deconjugation of macrocyclic α,β-unsaturated esters by sequential amidation and olefin transposition: Application to enantioselective phase-transfer catalysis

Article abstract of DOI:10.1039/c9ob01355e

The stereoselective synthesis of chiral macrocycles bearing two aliphatic amide functional groups is reported. After the amidation mediated by TBD, a guanidine derivative, the olefin transposition step is performed with a slight excess of t-BuOK. The products are afforded in moderate to good combined yields (up to 59%) and with an excellent syn diastereoselectivity (dr > 49:1). Introducing enantiopure α-branched substituents was possible and it resulted in mixtures of diastereomers, which could be tested as phase-transfer catalysts using the formation of a phenylalanine analog as a test reaction (up to 43% ee). A clear matched-mismatched situation was observed in the two diastereomeric series.

Full text of DOI:10.1039/c9ob01355e

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DOI: 10.1039/C9OB01355E
Journal Name
ARTICLE
Stereoselective deconjugation of macrocyclic α,β-unsaturated
esters by sequential amidation and olefin transposition:
application to enantioselective phase-transfer catalysis
Received 00th January 20xx,
Accepted 00th January 20xx
Alexandre Homberg,a Radim Hrdina,a Mahesh Vishe,a Laure Guénée,b Jérôme Lacour*a
DOI: 10.1039/x0xx00000x
The stereoselective synthesis of chiral macrocycles bearing two aliphatic amide functional groups is reported. After the
amidation mediated by TBD, a guanidine derivative, the olefin transposition step is performed with a slight excess of t-BuOK.
The products are afforded in moderate to good combined yields (up to 59%) and with an excellent syn diastereoselectivity
(dr > 49:1). Introducing enantiopure α-branched substituents was possible and it resulted in mixtures of diastereomers,
which could be tested as phase-transfer catalysts using the formation of a phenylalanine analog as a test reaction (up to
43% ee). A clear matched-mismatched situation was observed in the two diastereomeric series.
www.rsc.org/
right). A two-step process is this time necessary. Amine
additions are mediated by TBD (1,5,7-triaza bicyclo[4.4.0]dec-5-
ene), a guanidine derivative that helps the formation of the α,β-
Introduction
In unsaturated esters, olefin transposition from α,β to β,γ-
positions is thermodynamically disfavored. To promote this
deconjugation, various protocols are usually employed which
utilize photochemical1 or strongly basic2 conditions to generate
dienol(ate) intermediates (Scheme 1A). Subsequent
(enantioselective) protonation in α position leads to the β,γ-
unsaturated esters.3 In that context, our group recently
reported the remote stereoselective deconjugations of bis-α,β-
unsaturated macrocycle 1 in presence of an excess of aromatic
amines and t-BuOK.4 In a single step, chiral polyether
macrocycles of type 2 are formed by a double tandem
[amidation + olefin transposition] process (Scheme 1B, left).
Mechanistically, it is believed that the ester functions are first
transformed into amide groups. Then, irreversible olefin
unsaturated amide derivatives 4. Then, olefin transpositions
under basic conditions (t-BuOK) afford the corresponding chiral
macrocycles 3 with high syn diastereoselectivity (dr > 49:1,
yields up to 59%). Chiral enantiopure amines can be utilized
and, after preparation of the resulting diastereomers, the
macrocycles were used as phase-transfer catalysts. In the
enantioselective alkylation of a protected glycine (ee up to
43%), a clear matched-mismatched situation is observed in the
two diastereomeric series.
A
H
OH/O
OMe
H+

CO2Me
CO2Me
H
h or base
H+
dienol(ate)
transpositions occur to yield macrocycles
2 as single
stereoisomers (racemic, dr > 49:1). Various applications have
been developed for compounds 2. In fact, such bis(aromatic)
derivatives have been used as pH-independent nanosensor,5
heteroditopic receptors for salts,6 ratiometric luminescent or
reversible chiroptical switches7 and as circularly-polarized
R
this work
B
R
NH
4
O
O
O
double
amidation
O
O
MeO2C
O
O
O
O
O
1.
aliphatic amines
TBD
O
O
O
CO2Me
HN
R
O
1
electrochemiluminescent
emmiters.8
Herein,
the
R
double
reference 4
aromatic amines, base
R
stereoselective synthesis of macrocycles of type 3 bearing two
aliphatic amide functional groups is reported (Scheme 2B,
2.
t-BuOK
transposition
dr >49:1
R
R
R
R
R
HN
HN
O
H
O
O
O
NH
O
NH
a. Department of Organic Chemistry, University of Geneva, Quai Ernest Ansermet
30, 1211 Geneva 4, Switzerland.
O
O
O
O
O
*
H
*
b. Laboratory of Crystallography, University of Geneva, Quai Ernest Ansermet 24,
1211 Geneva 4, Switzerland.
O
O
O
O
O
O
H
H
2
3
c. Electronic Supplementary Information (ESI) available: Experimental conditions,
full characterizations, 1H NMR, 13C NMR and 19F NMR spectra of all new
compounds (PDF); CSP-HPLC traces; CCDC 1923025, 1923026 and 1923027. For
ESI and crystallographic data in CIF or other electronic format see
DOI: 10.1039/x0xx00000x. In addition, the dataset for this article can be found at
the following DOI: 10.26037/yareta:fp326563trgt3gp3l3ofsyfiem. It will be
preserved for 10 years.
> 19 examples
> up to 59% combined yield
> enantioselective phase-transfer catalysis
>
Scheme 1 Typical conditions for the deconjugation of α,β-unsaturated esters (A). Remote
stereoselective synthesis of chiral polyether macrocycles (B, syn transposition, dr > 49:1).
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 1
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chiral cis-diastereoisomer (racemic) is formedViedwuArrtiinclge Ontlhinee
reaction and traces of the achiral (meso, trans) stereoisomer
Results and discussion
Initial attempts
DOI: 10.1039/C9OB01355E
could not be detected. This result indicates that the mechanism
for the olefin transposition(s) is similar to that previously
reported;4 the potassium ion acts as a template and helps relay
the second reprotonation on the same prochiral face than the
first one.
Previously, it was shown that methyl α-diazo-β-ketoester reacts
with 1,4-dioxane under dirhodium catalysis in a formal
[3+6+3+6] multi-component condensation. The process is mild
and affords the resulting unsaturated macrocycle 1 on multi-
gram scale (up to 20 grams) while using a low catalyst loading
(0.01-0.001 mol%).9,10 As mentioned earlier, compound 1 reacts
with excesses of ArNH2 and t-BuOK (> 3 equiv each) to yield
unsaturated bis(aromatic) derivatives 2. This reaction tolerates
a large variety of aromatic amines.4-8, 11 However, despite major
efforts in the group, it was never possible to achieve the
analogous 1 → 3 transformation with aliphatic amines instead
of anilines. Of the two consecutive steps, it was clearly the first
one that was problematic under the previous conditions. Care
was thus taken to decouple the two steps of the process and
perform the amide formation first, prior to the olefin
transposition.
Table 1 Amidation of 1: optimization
O
Ph
NH
O
Ph
(4 equiv)
NH2
MeO2C
O
O
O
O
O
O
O
O
O
O
reagent, time
THF, 60 °C
CO2Me
O
O
HN
Ph
1
4a
Cl
Cl
N
Mes
Mes
Mes
Mes
N
N
N
N
N
N
H
IMes·HCl
SIMes·HCl
TBD
Entry
Reagent (equiv)
Time (h)
15
3
Isolated yield
no conv.
degradation
< 30% conv.[b]
no conv.
no conv.
no conv.
no conv.
no conv.
1
2[a]
3[a]
4
5
6
7
8
9
10
11
12
13
-
Optimization of the two-step process
t-BuOK (4)
n-BuLi (4)
Yb(OTf)3 (0.1)
Yb(OTf)3 (2)
BF3·OEt2 (0.2)
BF3·OEt2 (2)
3
For the transformation of macrocycle 1 into the corresponding
,-unsaturated bis(aliphatic) macrocycles 4, mild conditions of
amidation were looked for. With regular non-activated esters,12
it is required to use additives to promote the reaction such as
(Lewis) acids,13 bases,14 metal salts and complexes,15 enzymes16
or organocatalysts.17 Many such conditions were tested using
macrocycle 1 and benzyl amine as model substrate and reagent
respectively (Table 1). Heating the macrocycle and the amine in
THF at 60 °C did not provoke a conversion (entry 1). Strongly
basic conditions, t-BuOK or n-BuLi, led either to a total
degradation or a partial 30% conversion of macrocycle 1
15
15
15
15
15
15
15
15
4
IMes·HCl/ t-BuOK (0.05)
IMes·HCl/ t-BuOK (2)
SIMes·HCl/ t-BuOK (2)
TBD (0.2)
degradation
degradation
no conv.
TBD (2)
TBD (2)
47%
75%
15
[a] -100 °C (1 min), then 25 °C instead of 60 °C; [b] the isolation of 4a was attempted
respectively (entries 2-3). Lewis acids (Yb(OTf)3, BF3·OEt2) and but failed; Abbreviations: Mes = mesityl.
N-heterocyclic carbenes were also tested (entries 4-10). In
many instances, a lack of reactivity was observed. Otherwise, it
A
B
was a full degradation of 1. Previously, for the transformation
of esters into amides, Mioskowski and collaborators used 1,5,7-
triazabicyclo [4.4.0]dec-5-ene (TBD) as catalyst.17g, 18, 19, 20 Using
20 mol% of this cyclic guanidine base, an amidation could not
be observed (entry 11).21 However, with a stoichiometric
amount of it (2 equiv), macrocycle 4a was obtained in a
satisfactory yield (47%) after 4 hours of reaction and a simple
filtration (entry 12). Increasing the reaction time to 15 hours
afforded 4a in 75% yield (entry 10). The structure of 4a was
confirmed by NMR spectroscopy and X-ray diffraction analysis
(see Figure 1A).
Ph
NH
Ph
O
Ph
NH
O
O
NH
O
O
O
O
O
O
+
O
O
Na
O
O
O
O
HN
4a
Ph
O
Na·3a +
[
]
Next, the olefin transposition of compound 4a was considered
under basic conditions.4 After optimization (Table S1), it was
found that the combination of t-BuOK (2.2 equiv) and 1,4-
dioxane as solvent afforded the best conditions.22 Macrocycle
3a was isolated in good yield (65%, Scheme 2) as a single
diastereoisomer (dr >49:1, 1H NMR monitoring). Once, again, an
effective remote stereoselectivity is noticed in this type of
process.4 The relative configuration of 3a was determined by
the solid state structure of the sodium BArF (tetrakis[3,5-
bis(trifluoromethyl)phenyl]borate) adduct (Figure 1B). Only the
Fig. 1 Stick view of the crystal structure of 4a and [Na·3a][BArF] (BArF anion and
hydrogens atoms are hidden for clarity).
Ph
O
Ph
NH
Ph
NH
O
HN
O
H
O
O
O
O
O
t-BuOK (2.2 equiv)
O
O
O
O
1,4-dioxane
15 hours, 25 °C
O
O
O
O
HN
Ph
H
4a
3a
65%, dr >49:1
2 | J. Name., 2012, 00, 1-3
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ARTICLE
Scheme 2 Base-induced olefin transposition of 4a to form 3a.
Table 2 Combined yields (two steps) of macrocycles 3a-3s
View Article Online
DOI: 10.1039/C9OB01355E
R
R
In solution, compounds 3 differ from the bis-anilide derivatives
2. In fact, in terms of simple host-guest chemistry, it had been
previously observed that a water molecule is usually complexed
inside the cavity of macrocycles 2.4 Herein, in chloroform-d,
there is little of interaction of 3a with water as monitored by 1H
NMR spectroscopy at different concentrations (8-116 mM, see
ESI). In comparison with the aniline series (compounds 2), the
proton signals of the amide groups or of the water molecule are
only weakly perturbed.
O
aliphatic amine
TBD, THF, 60 °C
1)
HN
O
H
O
NH
O
MeO2C
O
O
O
O
O
O
-BuOK
2) t
CO2Me
O
O
1,4-dioxane, 25 °C
O
O
H
3
1
dr >49:1
method A (linear amines): [a]

[b]
method B (enantiopure series, dr 1.4:1):
R2
R2
R1
HN
Ar
(S)
R1
NH
O
Ar
(S)
O
H
O
HN
O
H
O
NH
O
O
O
O
O
*
O
O
O
O
O
O
*
H
2-Step process: Scope and (lack of) asymmetric induction with
enantiopure amines
H
R2 = Me, Ar = Ph, : 25%
3k
R1 = Bn, : 54%
3a
R2 = Et, Ar = Ph, : 15%
3l
R1 = Me, : 46%
3b
R2 = Me, Ar = p-OMeC6H4,
: 35%
With the optimal conditions for the amidation and the olefin
transposition in hand, various linear and α-branched amines
were introduced. In Table 2, the yields are reported for the two
steps. In general, with linear primary amines, moderate to good
combined yields were obtained (35-55%); the nature of the side
chains has little influence on the outcome. For the standard
reaction, macrocycle 3a was obtained in 54% overall yield.
Methyl, propyl, octyl and allyl substituted derivatives 3b to 3e
were obtained in similar yields (42%-55%). Silyl or methyl
protected amino alcohols were used and afforded macrocycles
3f to 3h in 35% to 54% yield.23
3m
R1 = n-Pr, : 42%
R1 = n-Oct, 3d: 55%
3c
R2 = Me, Ar = 1-naphthyl, : 20%
3n
R2 = Me, Ar = 2-naphthyl, : 15%
3o
R1 = allyl, : 44%
3e
R1 = (CH2)2OTBS, , 35%
R2
3f
R2
Ar
(R)
Ar
R1 = (CH2)2OMe, , 54%
3g
(R)
R1 = (CH2)3OMe, , 54%
NH
O
HN
O
H
O
3h
O
O
*
method B (-branched achiral amines): [b]
O
O
O
*
H
R1 = i-Pr, , 29%
R2 = Me, Ar = Ph, : 25%
3i
3p
R1 = c-Hex, , 18%
R2 = Et, Ar = Ph, : 15%
3j
3q
R2 = Me, Ar = p-FC6H4, : 35%
R2 = Me, Ar = 1-naphthyl, : 20%
3r
3s
[a] Method A: 1 (0.25 mmol), linear amine (4.0 equiv), TBD (2.0 equiv), THF, 60 °C, 15
hours; then t-BuOK (2.2 equiv), dioxane, 25 °C, 15 hours. [b] Method B: 1 (0.25 mmol),
α-branched amine (4.0 equiv), TBD (4.0 equiv), THF, 60 °C, 10 days; then t-BuOK (2.2
equiv), dioxane, 25 °C, 15 hours. Macrocycles 3k to 3s are obtained as mixtures of
diastereoisomers (1:1 ≤ dr ≤ 1.4:1, see ESI).
However, when the introduction of α-branched amines was
investigated under the above conditions, only poor conversions
were observed for the first amidation step; the sterically-
hindered amines being much less reactive. It was necessary to
increase both the amount of TBD (from 2 to 4 equiv) and the
reaction time (15 hours to 10 days) to reach full conversion of
1. Then, upon transposition with t-BuOK, macrocycles 3i (i-Pr)
and 3j (c-Hex) were obtained in moderate combined yields (29%
and 18% respectively). Similarly, with enantiopure α-alkyl
substituted benzyl or methylnaphthyl amines, we could isolate
the corresponding macrocycles 3k to 3s (15-35%). In all these
reactions, the critical step in terms of yield is not the
transposition but the amidation. In fact, a slow competitive
degradation of starting macrocycle 1 occurs during the
amidation that disfavors the overall process.24
Finally, care was taken to study the stereochemical outcome of
the reaction in the presence of enantiopure -branched
amines.25 Satisfactorily, the double transposition still occurs
with a syn stereoselectivity but it leads, this time, to two
different products. Indeed, the enantiopure amine residues
exert little influence on the newly created stereogenic centers
inside the macrocyclic skeleton and two diastereoisomers are
formed. For instance, with (S)-phenylethylamine, product 3k
exists in two different (S,S,S,S) and (S,R,R,S) configurations with
a low overall stereoselectivity (dr 1.3:1).26 Several other amines
were tested and the selectivity has remained low in all cases (dr
≤ 1.4:1). In Table 2, the yields are given for the two steps and
both diastereoisomers together; the stereoisomers were
separated in only in one instance (see next paragraph).
Application: Enantioselective phase-transfer catalysis
Crown ethers, thanks to their ability to complex alkali metal
salts and render them soluble in both polar and apolar
solutions, are efficient phase-transfer catalysts (PTCs). Several
chiral non-racemic versions of these derivatives have been
developed and applied in various enantioselective reactions
such as alkylations, 1,4-additions or oxidations.27 It was then
logical to test compounds 3k to 3s bearing α-branched
enantiopure substituents as PTCs. We selected the alkylation of
protected glycine 5 with benzyl bromide which affords chiral
phenylalanine derivative 6 as product as benchmark; this
reaction occurring only in the presence of catalysts (Table 3,
entry 1).28 The different macrocycles were reacted under
conditions that are standard for phase-transfer catalysis with
chiral crown ethers (Tables S2-S5). Overall and not surprisingly,
it was found that sodium and potassium salts afforded the best
conversions (Tables S3). A rather large screening of solvents was
also performed and CH2Cl2 was most favorable followed by 1,1-
dichloroethane and 1,1,1-trichloroethane; similar ee values
being however observed (Tables S5). With derivative 3k as
catalyst (5 mol%, Table 3, entry 2), amino acid (+)-6 was
obtained in good yield (86%) and low enantioselectivity (17%
ee). The increase of catalyst loading to 10 mol% improved
slightly the enantiomeric excess to 21% (entry 3). With toluene
as solvent, longer reaction time, lower enantioselectivity and a
reversal of the stereoinduction in favor of the antipodal
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Journal Name
enantiomer (–)-6 were observed (entry 4). Using macrocycle 3p
(with an inverted configuration on the amide side chain),
analogous results to 3k were obtained in favor of the
levorotatory enantiomer. It was then shown that 1-naphthyl
derivative 3n is the most efficient of the series (see ESI). Using
3n as PTC (10 mol%, dr 1.4:1) at 25 °C, amino acid (+)-6 was
obtained in good yield (86%) and moderate enantioselectivity
(32% ee) (Table 3, entry 6). Decreasing the temperature to 10 °C
improved slightly the enantiomeric excess (39% ee, entry 7).
The two diastereoisomers of 3n, namely (S,S,S,S)-3n (major) and
(S,R,R,S)-3n (minor), could be separated by column
chromatography (SiO2, CH2Cl2/MeOH gradient) and used
independently in the phase-transfer reaction. The configuration
of (S,S,S,S)-3n was ascertained by the X-ray structural analysis
of the NaBArF salt. With (S,S,S,S)-3n, the dextrorotatory
enantiomer of 6 was again favored with a slightly improved
enantiomeric excess (43% ee, entry 8). Higher catalyst loading
(20 mol%) or temperature decrease (0 °C) did not lead to a
larger enantioinduction (entries 9 and 10). Interestingly, using
minor diastereoisomer (S,R,R,S)-3n and after a longer reaction
time (48 hours), the antipodal enantiomer (–)-6 was obtained in
86% yield and only a 13% ee value (entry 11). The difference of
reactivity and selectivity between the two diastereoisomers of
3n illustrates thus a clear matched-mismatched situation in the
enantioselective alkylation of glycine 5.
Conclusion
Starting from readily prepared unsaturated
View Article Online
DOI: 10.1039m/Ca9OcrBo0c1y3c5l5iEc
precursor 1, chiral crown ethers bearing two aliphatic amide
functional groups were synthetized. It was necessary to
separate the amidation (mediated by TBD) and the olefin
transposition step (induced by a slight excess of t-BuOK). The
products were afforded in moderate to good combined yields
(up to 59%) and with an excellent syn diastereoselectivity (dr >
49:1). Introducing enantiopure α-branched substituents was
possible and resulted in mixtures of diastereomers, which could
be tested as phase-transfer catalysts using the formation of
enantioenriched phenylalanine analogs as a benchmark (up to
43% ee). In this reaction, a clear matched-mismatched situation
was observed in the two diastereomeric series.
Conflicts of interest
There are no conflicts to declare.
Acknowledgements
We thank the University of Geneva and the Swiss National
Science Foundation for financial support (SNF 200020-172497
and 200020-184843). We acknowledge the contributions of the
Sciences Mass Spectrometry (SMS) platform at the Faculty of
Sciences, University of Geneva. We thank Professor Dr Klaus
Ditrich (BASF) for generous gifts of the chiral enantiopure
amines.
Table 3 Asymmetric phase-transfer catalysis with 3n [a]
BnBr (1.2 equiv)
mol%
Ph
Ph
N
Ph
catalyst (
)
*
O
O
Ph
Ph
N
aq. NaOH (50% w/v)
CH2Cl2, (3:1 org/aq)
temperature, time
O
O
5
6
86%,
Notes and references
1
(a) F. Bargiggia and O. Piva, Tetrahedron Asymmetry, 2003, 14,
1819-1827; (b) T. Bach and F. Höfer, J. Org. Chem., 2001, 66,
3427-3434; (c) O. Piva, J. Org. Chem., 1995, 60, 7879-7883; (d)
O. Piva and J.-P. Pete, Tetrahedron Asymmetry, 1992, 3, 759-
768; (e) R. Mortezaei, D. Awandi, F. Henin, J. Muzart and J. P.
Pete, J. Am. Chem. Soc., 1988, 110, 4824-4826; (f) S. L. Eng, R.
Ricard, C. S. K. Wan and A. C. Weedon, J. Chem. Soc. Chem.
Commun., 1983, 236-238; (g) J. R. Scheffer and B. A. Boire, J.
Am. Chem. Soc., 1971, 93, 5490-5495; (h) M. J. Jorgenson, J.
Am. Chem. Soc., 1969, 91, 198-200; (i) G. Buechi and S. H.
Feairheller, J. Org. Chem., 1969, 34, 609-612; (j) R. R. Rando
and W. v. E. Doering, J. Org. Chem., 1968, 33, 1671-1673; (k)
M. J. Jorgenson and T. Leung, J. Am. Chem. Soc., 1968, 90,
3769-3774; (l) M. J. Jorgenson and N. C. Yang, J. Am. Chem.
Soc., 1963, 85, 1698-1699.
(S)
HN
(S)
(S)
(S)
NH
HN
O
O
O
O
NH
O
O
H
H
(S) O
O
O (R)
O
O
O
O
O
H
H
(R)
O
O
(S)
(S,S,S,S)-3n
(S,R,R,S)-3n
major diastereomer
minor diastereomer
Entry
1
2
3
4[c]
5
6
7
8
9
Catalyst (mol%)
- (blank)
Temp (°C)
Time (h)
15
15
15
96
15
15
15
15
ee (%)
-
[b]
25
25
25
25
25
25
10
10
10
0
3k (5)
3k (10)
3k (5)
3p (5)
3n (10)
3n (10)
17
21
-12
-17
32
39
43
42
42
2
3
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(S,S,S,S)-3n (10)
(S,S,S,S)-3n (20)
(S,S,S,S)-3n (10)
(S,R,R,S)-3n (10)
15
15
48
10
11
10
-13
[a] For all catalyzed reactions, yields are consistent in the range of 85-87%. [b] No
conversion of 5. [c] In toluene instead of CH2Cl2.
4 | J. Name., 2012, 00, 1-3
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10 Macrocycles of different scaffolds or sizes can be obtained
using similar Rh(II)-catalyzed procedures by condensation of
α-diazo-β-ketoesters with other small cyclic ethers such as
THP, THF, oxetane, oxepane or morpholines. See reference 9
11 M. Vishe, T. Lathion, S. Pascal, O. Yushchenko, A. Homberg, E.
Brun, E. Vauthey, C. Piguet and J. Lacour, Helv. Chim. Acta, 19 For the TBD mediated synthesis of carbamate and urea see:
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(a) S. Carloni, D. E. De Vos, P. A. Jacobs, R. Maggi, G. Sartori
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isomerization.
V. M. de Oliveira, R. Silva de Jesus, A. F. Gomes, F. C. Gozzo, A. 23 The isomerization does not proceed with unprotected alcohol
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View Article Online
DOI: 10.1039/C9OB01355E
R
R
1. aliphatic amines, TBD
O
HN
O
O
NH
2. t-BuOK
MeO2C
O
O
O
O
O
O
O
*
H
*
O
CO2Me
O
O
H
O
> 19 examples
> syn diastereoselectivity (dr > 49:1)
> two-step process
> up to 59% combined yield
> enantioselective phase-transfer catalysis
6 | J. Name., 2012, 00, 1-3
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